Basic Research in Cardiology最新文献

{"title":"Gasotransmitters and noble gases in cardioprotection: unraveling molecular pathways for future therapeutic strategies.","authors":"Pasquale Pagliaro, Nina C Weber, Saveria Femminò, Giuseppe Alloatti, Claudia Penna","doi":"10.1007/s00395-024-01061-1","DOIUrl":"10.1007/s00395-024-01061-1","url":null,"abstract":"<p><p>Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"509-544"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise training decreases lactylation and prevents myocardial ischemia-reperfusion injury by inhibiting YTHDF2.","authors":"Gui-E Xu, Pujiao Yu, Yuxue Hu, Wensi Wan, Keting Shen, Xinxin Cui, Jiaqi Wang, Tianhui Wang, Caiyue Cui, Emeli Chatterjee, Guoping Li, Dragos Cretoiu, Joost P G Sluijter, Jiahong Xu, Lijun Wang, Junjie Xiao","doi":"10.1007/s00395-024-01044-2","DOIUrl":"10.1007/s00395-024-01044-2","url":null,"abstract":"<p><p>Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N⁶-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m⁶A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m⁶A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"651-671"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotection in cardiovascular surgery.","authors":"Sharif A Sabe, Dwight D Harris, Mark Broadwin, Frank W Sellke","doi":"10.1007/s00395-024-01062-0","DOIUrl":"10.1007/s00395-024-01062-0","url":null,"abstract":"<p><p>Since the invention of cardiopulmonary bypass, cardioprotective strategies have been investigated to mitigate ischemic injury to the heart during aortic cross-clamping and reperfusion injury with cross-clamp release. With advances in cardiac surgical and percutaneous techniques and post-operative management strategies including mechanical circulatory support, cardiac surgeons are able to operate on more complex patients. Therefore, there is a growing need for improved cardioprotective strategies to optimize outcomes in these patients. This review provides an overview of the basic principles of cardioprotection in the setting of cardiac surgery, including mechanisms of cardiac injury in the context of cardiopulmonary bypass, followed by a discussion of the specific approaches to optimizing cardioprotection in cardiac surgery, including refinements in cardiopulmonary bypass and cardioplegia, ischemic conditioning, use of specific anesthetic and pharmaceutical agents, and novel mechanical circulatory support technologies. Finally, translational strategies that investigate cardioprotection in the setting of cardiac surgery will be reviewed, with a focus on promising research in the areas of cell-based and gene therapy. Advances in this area will help cardiologists and cardiac surgeons mitigate myocardial ischemic injury, improve functional post-operative recovery, and optimize clinical outcomes in patients undergoing cardiac surgery.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"545-568"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection.","authors":"Edoardo Bertero, Tudor-Alexandru Popoiu, Christoph Maack","doi":"10.1007/s00395-024-01060-2","DOIUrl":"10.1007/s00395-024-01060-2","url":null,"abstract":"<p><p>Mitochondrial calcium (Ca²⁺) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca²⁺ levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca²⁺ in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca²⁺ handling by regulating the activity of the main Ca²⁺ influx and efflux pathways, i.e., the mitochondrial Ca²⁺ uniporter and sodium/Ca²⁺ exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"569-585"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone marrow cells contribute to seven different endothelial cell populations in the heart.","authors":"Parisa Shabani, Vahagn Ohanyan, Ammar Alghadeer, Daniel Gavazzi, Feng Dong, Liya Yin, Christopher Kolz, Lindsay Shockling, Molly Enrick, Ping Zhang, Xin Shi, William Chilian","doi":"10.1007/s00395-024-01065-x","DOIUrl":"10.1007/s00395-024-01065-x","url":null,"abstract":"<p><p>Understanding the mechanisms underlying vascular regeneration in the heart is crucial for developing novel therapeutic strategies for myocardial ischemia. This study investigates the contribution of bone marrow-derived cells to endothelial cell populations in the heart, and their role in cardiac function and coronary circulation following repetitive ischemia (RI). Chimeric rats were created by transplanting BM cells from GFP female rats into irradiated male recipients. After engraftment chimeras were subjected to RI for 17 days. Vascular growth was assessed from recovery of cardiac function and increases in myocardial blood flow during LAD occlusion. After sorting GFP⁺ BM cells from heart and bone of Control and RI rats, single-cell RNA sequencing was implemented to determine the fate of BM cells. Our in vivo RI model demonstrated an improvement in cardiac function and myocardial blood flow after 17 days of RI with increased capillary density in the rats subjected to RI compared to Controls. Single-cell RNA sequencing of bone marrow cells isolated from rats' hearts identified distinct endothelial cell (EC) subpopulations. These ECs exhibited heterogeneous gene expression profiles and were enriched for markers of capillary, artery, lymphatic, venous, and immune ECs. Furthermore, BM-derived ECs in the RI group showed an angiogenic profile, characterized by upregulated genes associated with blood vessel development and angiogenesis. This study elucidates the heterogeneity of bone marrow-derived endothelial cells in the heart and their response to repetitive ischemia, laying the groundwork for targeting specific subpopulations for therapeutic angiogenesis in myocardial ischemia.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"699-715"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury.","authors":"Jiro Abe, Ana Vujic, Hiran A Prag, Michael P Murphy, Thomas Krieg","doi":"10.1007/s00395-024-01063-z","DOIUrl":"10.1007/s00395-024-01063-z","url":null,"abstract":"<p><p>The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"691-697"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43^Cre-ER(T)/fl mice by altering the coenzyme Q pool.","authors":"Marta Consegal, Elisabet Miró-Casas, Ignasi Barba, Marisol Ruiz-Meana, Javier Inserte, Begoña Benito, Cristina Rodríguez, Freddy G Ganse, Laura Rubio-Unguetti, Carmen Llorens-Cebrià, Ignacio Ferreira-González, Antonio Rodríguez-Sinovas","doi":"10.1007/s00395-024-01052-2","DOIUrl":"10.1007/s00395-024-01052-2","url":null,"abstract":"<p><p>Succinate accumulates during myocardial ischemia and is rapidly oxidized during reperfusion, leading to reactive oxygen species (ROS) production through reverse electron transfer (RET) from mitochondrial complex II to complex I, and favoring cell death. Given that connexin 43 (Cx43) modulates mitochondrial ROS production, we investigated whether Cx43 influences RET using inducible knock-out Cx43^Cre-ER(T)/fl mice. Oxygen consumption, ROS production, membrane potential and coenzyme Q (CoQ) pool were analyzed in subsarcolemmal (SSM, expressing Cx43) and interfibrillar (IFM) cardiac mitochondria isolated from wild-type Cx43^fl/fl mice and Cx43^Cre-ER(T)/fl knock-out animals treated with 4-hydroxytamoxifen (4OHT). In addition, infarct size was assessed in isolated hearts from these animals submitted to ischemia-reperfusion (IR), and treated or not with malonate, a complex II inhibitor attenuating RET. Succinate-dependent ROS production and RET were significantly lower in SSM, but not IFM, from Cx43-deficient animals. Mitochondrial membrane potential, a RET driver, was similar between groups, whereas CoQ pool (2.165 ± 0.338 vs. 4.18 ± 0.55 nmol/mg protein, p < 0.05) and its reduction state were significantly lower in Cx43-deficient animals. Isolated hearts from Cx43^Cre-ER(T)/fl mice treated with 4OHT had a smaller infarct size after IR compared to Cx43^fl/fl, despite similar concentration of succinate at the end of ischemia, and no additional protection by malonate. Cx43 deficiency attenuates ROS production by RET in SSM, but not IFM, and was associated with a decrease in CoQ levels and a change in its redox state. These results may partially explain the reduced infarct size observed in these animals and their lack of protection by malonate.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"673-689"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidation-reduction imaging of myoglobin reveals two-phase oxidation in the reperfused myocardium.","authors":"Sally Badawi, Clémence Leboullenger, Matthieu Chourrout, Yves Gouriou, Alexandre Paccalet, Bruno Pillot, Lionel Augeul, Radu Bolbos, Antonino Bongiovani, Nathan Mewton, Thomas Bochaton, Michel Ovize, Meryem Tardivel, Mazen Kurdi, Emmanuelle Canet-Soulas, Claire Crola Da Silva, Gabriel Bidaux","doi":"10.1007/s00395-024-01040-6","DOIUrl":"10.1007/s00395-024-01040-6","url":null,"abstract":"<p><p>Myocardial infarction (MI) is a serious acute cardiovascular syndrome that causes myocardial injury due to blood flow obstruction to a specific myocardial area. Under ischemic-reperfusion settings, a burst of reactive oxygen species is generated, leading to redox imbalance that could be attributed to several molecules, including myoglobin. Myoglobin is dynamic and exhibits various oxidation-reduction states that have been an early subject of attention in the food industry, specifically for meat consumers. However, rarely if ever have the myoglobin optical properties been used to measure the severity of MI. In the current study, we develop a novel imaging pipeline that integrates tissue clearing, confocal and light sheet fluorescence microscopy, combined with imaging analysis, and processing tools to investigate and characterize the oxidation-reduction states of myoglobin in the ischemic area of the cleared myocardium post-MI. Using spectral imaging, we have characterized the endogenous fluorescence of the myocardium and demonstrated that it is partly composed by fluorescence of myoglobin. Under ischemia-reperfusion experimental settings, we report that the infarcted myocardium spectral signature is similar to that of oxidized myoglobin signal that peaks 3 h post-reperfusion and decreases with cardioprotection. The infarct size assessed by oxidation-reduction imaging at 3 h post-reperfusion was correlated to the one estimated with late gadolinium enhancement MRI at 24 h post-reperfusion. In conclusion, this original work suggests that the redox state of myoglobin can be used as a promising imaging biomarker for characterizing and estimating the size of the MI during early phases of reperfusion.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"435-451"},"PeriodicalIF":7.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11142982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a mechanism promoting mitochondrial sterol accumulation during myocardial ischemia-reperfusion: role of TSPO and STAR.","authors":"Juliette Bréhat, Shirin Leick, Julien Musman, Jin Bo Su, Nicolas Eychenne, Frank Giton, Michael Rivard, Louis-Antoine Barel, Chiara Tropeano, Frederica Vitarelli, Claudio Caccia, Valerio Leoni, Bijan Ghaleh, Sandrine Pons, Didier Morin","doi":"10.1007/s00395-024-01043-3","DOIUrl":"10.1007/s00395-024-01043-3","url":null,"abstract":"<p><p>Hypercholesterolemia is a major risk factor for coronary artery diseases and cardiac ischemic events. Cholesterol per se could also have negative effects on the myocardium, independently from hypercholesterolemia. Previously, we reported that myocardial ischemia-reperfusion induces a deleterious build-up of mitochondrial cholesterol and oxysterols, which is potentiated by hypercholesterolemia and prevented by translocator protein (TSPO) ligands. Here, we studied the mechanism by which sterols accumulate in cardiac mitochondria and promote mitochondrial dysfunction. We performed myocardial ischemia-reperfusion in rats to evaluate mitochondrial function, TSPO, and steroidogenic acute regulatory protein (STAR) levels and the related mitochondrial concentrations of sterols. Rats were treated with the cholesterol synthesis inhibitor pravastatin or the TSPO ligand 4'-chlorodiazepam. We used Tspo deleted rats, which were phenotypically characterized. Inhibition of cholesterol synthesis reduced mitochondrial sterol accumulation and protected mitochondria during myocardial ischemia-reperfusion. We found that cardiac mitochondrial sterol accumulation is the consequence of enhanced influx of cholesterol and not of the inhibition of its mitochondrial metabolism during ischemia-reperfusion. Mitochondrial cholesterol accumulation at reperfusion was related to an increase in mitochondrial STAR but not to changes in TSPO levels. 4'-Chlorodiazepam inhibited this mechanism and prevented mitochondrial sterol accumulation and mitochondrial ischemia-reperfusion injury, underlying the close cooperation between STAR and TSPO. Conversely, Tspo deletion, which did not alter cardiac phenotype, abolished the effects of 4'-chlorodiazepam. This study reveals a novel mitochondrial interaction between TSPO and STAR to promote cholesterol and deleterious sterol mitochondrial accumulation during myocardial ischemia-reperfusion. This interaction regulates mitochondrial homeostasis and plays a key role during mitochondrial injury.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"481-503"},"PeriodicalIF":7.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140189474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside.","authors":"Y Xiao, Q Wang, H Zhang, R Nederlof, D Bakker, B A Siadari, M W Wesselink, B Preckel, N C Weber, M W Hollmann, B V Schomakers, M van Weeghel, C J Zuurbier","doi":"10.1007/s00395-024-01042-4","DOIUrl":"10.1007/s00395-024-01042-4","url":null,"abstract":"<p><p>Decreased nicotinamide adenine dinucleotide (NAD⁺) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD⁺ precursor due to efficient NAD⁺ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and ¹³C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) (\"mild glycolysis group\"), (b) lactate + pyruvate + FA (\"no glycolysis group\"), or (c) glucose + FA + insulin (\"high glycolysis group\"). NR increased cardiac NAD⁺ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the \"no glycolysis\" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high ¹³C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining \"no glycolysis\" hearts or \"high glycolysis\" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"403-418"},"PeriodicalIF":7.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11142987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}